The administration of physiologically active substances to a mammalian host is a complicated matter which requires the consideration of numerous factors for in vivo efficacy. For example, for a physiologically active substance to be therapeutically effective in vivo, it must be able (in most situations) to bind to a specific target molecule, so as to inhibit or activate the physiological activity of that target molecule. Binding to a target molecule, however, requires that the physiologically active substance either be capable of direct administration at the target site or be capable of being administered elsewhere and subsequently transported to the target site without significant loss of therapeutic activity. Unfortunately, various problems arise in the administration and transport of physiologically active substances in mammals.
For example, many therapeutic drugs are often administered orally or intravascularly. In the case of oral administration, for a drug to effectively reach the target site, the drug must not only survive the degradative processes associated with the mammalian gastrointestinal tract, but it must also be transported from the gastrointestinal tract into the host's vascular system. The problems associated with oral drug administration, therefore, often result in a significant reduction in in vivo therapeutic activity which, in turn, results in the presence of subtherapeutic doses of the drug for extended periods of time.
Unlike oral administration, when a drug is administered intravascularly, it is not subject to the degradative effects of the gastrointestinal tract nor the need for transport from the gastrointestinal tract into the vascular system. However, when administered intravascularly, drugs are still often subject to being confined to a compartment other than the region where the target site is, being eliminated through the degradative and excretory processes of the liver and kidneys and, depending upon the nature of the drug, being subject to the lymphocytic system.
Furthermore, in addition to the problems associated with degradation and transport of administered drugs in mammals, in order to provide for an effective therapeutic effect, one must also maintain a therapeutically effective amount of the drug in the vascular system over an extended period of time, where the drug is available for binding to the target. Unfortunately, however, many drugs are often poorly absorbed from the gastrointestinal tract and/or are rapidly cleared from the host's bloodstream, thereby resulting in severe limitations for the clinical applications of such drugs.
In attempts to overcome many of the problems associated with drug degradation and transport as well as attempting to maintain effective drug concentrations over extended periods of time, various drug administration regimens have been developed. For example, one common administration technique is giving a large bolus of the drug at periodic time intervals. This manner of administration, however, often results in subtherapeutic doses of the drug for extended periods of time followed by doses which may greatly exceed the desired therapeutic level. The latter may often involve serious adverse side effects.
Other efforts to avoid the problems associated with giving boluses have, in part, involved providing depots comprising the drug. For example, various pumps and biodegradable and non-biodegradable capsules have been devised for the delivery of drug over an extended period of time. These devices, however, also have a variety of shortcomings in their profile of drug delivery, for example, often resulting in an inflammatory response and/or being subject to interference in their release of active drug.
One class of drugs which is subject to many of the problems described above are those drugs that serve to inhibit the activity of the mammalian enzyme, renin. Such drugs function to inhibit endogenous renin activity, thereby affecting blood volume, pressure and the electrolyte balance of body fluids. The clinical application of these drugs, however, is severely limited by the fact that they are often poorly absorbed from the gastrointestinal tract and/or are rapidly cleared from the host's bloodstream.
There is, therefore, substantial interest in being able to provide for improved methods of providing for the continued maintenance of renin inhibitors in the bloodstream. The method as described herein involves the covalent linking of derivatized renin inhibitors to blood components for the purpose of enhancing the lifetime of the renin inhibitors in the vascular system. Although derivatized, the renin inhibitors retain activity when covalently bound to a blood component and provide renin inhibitory activity over an extended period of time as compared to that obtained with unconjugated drug.